Combination of metformin/efavirenz/fluoxetine exhibits profound anticancer activity via a cancer cell-specific ROS amplification.

The possible anticancer activity of combination (M + E + F) of metformin (M), efavirenz (E), and fluoxetine (F) was investigated in normal HDF cells and HCT116 human colon cancer cells. Metformin increased cellular FOXO3a, p-FOXO3a, AMPK, p-AMPK, and MnSOD levels in HDFs but not in HCT116 cells. Cellular ATP level was decreased only in HDFs by metformin. Metformin increased ROS level only in HCT116 cells. Transfection of si-FOXO3a into HCT116 reversed the metformin-induced cellular ROS induction, indicating that FOXO3a/MnSOD is the key regulator for cellular ROS level. Viability readout with M, E, and F alone decreased slightly, but the combination of three drugs dramatically decreased cell survival in HCT116, A549, and SK-Hep-1 cancer cells but not in HDF cells. ROS levels in HCT116 cells were massively increased by M + E + F combination, but not in HDF cells. Cell cycle analysis showed that of M + E + F combination caused cell death only in HCT116 cells. The combination of M + E + F reduced synergistically mitochondrial membrane potential and mitochondrial electron transport chain complex I and III activities in HCT116 cells when compared with individual treatments. Western blot analysis indicated that DNA damage, apoptosis, autophagy, and necroptosis-realated factors increased in M + E + F-treated HCT116 cells. Oral administration with M + E + F combination for 3 weeks caused dramatic reductions in tumor volume and weight in HCT116 xenograft model of nude mice when compared with untreated ones. Our results suggest that M + E + F have profound anticancer activity both in vitro and in vivo via a cancer cell-specific ROS amplification (CASRA) through ROS-induced DNA damage, apoptosis, autophagy, and necroptosis.

A Prosthetic Socket with Active Volume Compensation for Amputated Lower Limb.

Typically, the actual volume of the residual limb changes over time. This causes the prosthesis to not fit, and then pain and skin disease. In this study, a prosthetic socket was developed to compensate for the volume change of the residual limb. Using an inflatable air bladder, the proposed socket monitors the pressure in the socket and keeps the pressure distribution uniform and constant while walking. The socket has three air bladders on anterior and posterior tibia areas, a latching type 3-way pneumatic valve and a portable control device. In the paper, the mechanical properties of the air bladder were investigated, and the electromagnetic analysis was performed to design the pneumatic valve. The controller is based on a hysteresis control algorithm with a closed loop, which keeps the pressure in the socket close to the initial set point over a long period of time. In experiments, the proposed prosthesis was tested through the gait simulator that can imitate a human's gait cycle. The active volume compensation of the socket was successfully verified during repetitive gait cycle using the weight loads of 50, 70, and 90 kg and the residual limb model with a variety of volumes. It was confirmed that the pressure of the residual limb recovered to the initial state through the active control. The pressure inside the socket had a steady state error of less than 0.75% even if the volume of the residual limb was changed from -7% to +7%.